1,2-Dithiins are six-membered ring heterocyclic compounds having two contiguous CH groups of benzene replaced by two sulfur atoms. 1,2 Dithiin molecules have been the subject of intense investigations by theoretical chemists and spectroscopists due to their anti-aromatic non-planar ring system. Aihara, J. Bull. Chem. Soc. Jpn. 1990, 63, 2899-2903; Cirmiraglia, R. et al., J. Mol. Str (Theochem) 1991, 230, 287-293. Eight 1,2-dithiin-containing acetylenic compounds called thiarubrines have now been isolated from natural sources, primarily from the Asteraceae plants. Constabel, C. P.; Towers, G. H. N. Planta Medica 1989, 55, 35-37; Balza, F., et al., Phytochemistry 1990, 29, 2901; Towers G. H. N. et al., 1993, U.S. Pat. No. 5,202,348; Ellis, S., et al., Phytochemistry 1993, 33, 224-226. Among others of these eight, thiarubrine A (1) and thiarubrine B (2), isolated from the young leaves of Aspilia mossambicesis and A. plurisetta, have been shown to exhibit a wide spectrum of biological activity including antiviral and antibiotic activities. Balza, F. et al., Phytochemistry 1989, 28, 3523; Freeman, F. et al., Sulfur Rep. 1989, 9, 207-247; Freeman, F. Heterocycles 1990, 701-750; Schroth, W. et al., Angew. Chem., Int. Ed. Engl. 1967 6,698-699; Schroth, W. et al., Chem. 1965 5, 352.varies.353 and 353-354. ##STR1##
It is well known that acetylenic compounds themselves, whether derived from nature Bohlman, F., et al., "Naturally Occurring Acetylenes" 1973, Academic Press, London, or from synthesis, Merz. et al., 1972, Ger. Offen. No. 2,118,437, have antiinfective as well as cytotoxic properties. All the natural 1,2-dithiins (thiarubrines) have polyacetylene side chains at either C-3-or C-3 and C-6. No total synthesis of any of the eight natural 1,2-dithiins containing acetylenes (thiarubrines) has been achieved, nor has any biological data of 1,2-dithiins without acetylenes been reported. The presence of acetylenic bonds in the thiarubrines makes their total syntheses difficult to achieve. Additionally, the role of the acetylenic bonds in their noted antifungal activity remains unclear. The inherent cytotoxicity as well the thermal and light instability of the thiarubrines severely limits their potential therapeutic utility as human medicinals. In order to overcome this shortcoming, a series of novel 1,2-dithiins were synthesized without acetylenic sidechains, and biologically evaluated for potential utility as antiinfective agents.
The first synthesis of 1,2-dithiin and its 3,6-disubstituted analogues was reported by Schroth and coworkers in Germany in 1960's. Schroth, W. et al., Angew. Chem., Int. Ed. Engl. 1967 6,698-699; Schroth, W. et al., Chem. 1965 5, 352-353 and 353-354. This method was most useful for the synthesis of diary dithiins (Scheme I). Thus, treatment of 1,4-diphenyl-1,3-butadiyne (3) with 2 equivalents of benzylthiol in refluxing ethanol in the presence of KOH provided the bis-benzylthiol adduct (4) in 85% yield with virtually complete stereo- and regioselectivity. Reductive removal of two benzyl groups by the treatment of 4 with Na in liquid ammonia at -78.degree. C., followed by oxidative dithiin ring formation with K.sub.3 [Fe(CN).sub.6] provided the deeply red-colored 3,6-diphenyl-1,2-dithiin (5) in about 51% overall yield. ##STR2##
This method involving the reductive-removal of the benzyl group with sodium in liquid ammonia followed by oxidative ring closure with K3[Fe(CN) 6] is, however, less effective for the synthesis of 1,2-dithiins with non-aromatic substituents at 3- and 6-positions.